Cerebral ischemia constitutes a serious, potentially fatal threat to patients with pathological processes involving diminished cerebral perfusion. Platelet have been implicated both as etiologic agents in cerebral ischemia associated with thromboembolic vessel occlusion and as modulators of neural injury following an ischemic insult. However, it is unknown if, or by what mechanism, cerebral ischemia induces abnormalities in platelet function, thereby creating a vehicle for secondary brain injury during reperfusion or revascularization. Further, little information exists regarding the effects of transient ischemia on platelet function in the newborn. Therefore, the overall research goal of this project is to examine platelet reactivity in a clinically relevant model of intracranial hypertension and to determine if the response of neonatal lamb platelet differs from that of mature sheep. Global incomplete ischemia will be produced for 15 minutes by infusion of artificial CS, while the MAP is allowed to vary spontaneously and ICE adjusted accordingly. Baseline and serial measurements during 4 hours of reperfusion will permit evaluation of cerebral blood flow, cerebral oxygen consumption, platelet activation, aggregation and secretion. In AIM 2 we will determine the effects of cerebral ischemia on platelet reactivity in neonatal vs. mature animals by examining changes in platelet surface antigens, platelet aggregation and granule secretion. Changes in platelet surface glycoproteins at 2, 30 and 240 min. of reperfusion will be evaluated using flow cytometry. Ex vivo platelet aggregation and secretion studies will be performed on whole blood using impedance aggregometry and luminometry, respectively, at 2, 30 and 240 min. reperfusion. In AIM 3 and 4 will examine two potential mechanisms for ischemia-induced platelet dysfunction. We will determine if nitric acid or platelet-activating factor plays a role in platelet activation during ischemia/reperfusion in neonatal vs. mature sheep using nitric oxide synthase (L-NNA) and PAF (BN 52021) inhibitors, respectively. Findings from this study will provide physiologic rationale for nursing care of patients following cardiac arrest, trauma, stroke and cerebrovascular injury. Further, detections of chronologic age-related variation in post- ischemic platelet function will elucidate developmental differences which impact nursing therapeutics directed toward critically ill neonates.